LUIS ALBERTO DE PADUA COVAS LAGE
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/31 - Laboratório de Genética e Hematologia Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/31 - Laboratório de Genética e Hematologia Molecular, Hospital das Clínicas, Faculdade de Medicina
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- Clinical, Laboratory, and Genetic Features of Erdheim-Chester Disease Patients from Two Reference Centers in a Developing Country(2020) BRANDAO, Antonio Adolfo Guerra Soares; FATOBENE, Giancarlo; ABDO, Andre; LAGE, Luis Alberto De Padua Covas; BENDIT, Israel; NARDINELLI, Luciana; SIQUEIRA, Sheila Aparecida Coelho De; LEVY, Debora; PEREIRA, Juliana; REGO, Eduardo M.; ROCHA, Vanderson
- Splenic Marginal Zone Lymphoma (SMZL) - Outcomes, Prognostic Factors and Risk-Adapted Therapy in Resource-Poor Settings: Data from a Latin American Retrospective Cohort(2020) LAGE, Luis Alberto de Padua Covas; SANTOS, Felipe Faganelli Caboclo dos; GERVATAUSKAS, Kasys Meira; LEVY, Debora; MOREIRA, Frederico Rafael; COUTO, Samuel Campanelli Freitas; CULLER, Hebert Fabricio; COSTA, Renata Oliveira; ROCHA, Vanderson; PEREIRA, Juliana
- Risk adapted approach: How to treat splenic marginal zone lymphoma in resource-poor settings? - The real-life experience of a Brazilian cancer treatment center(2020) LAGE, Luis Alberto de Padua Covas; SANTOS, Felipe Faganelli Caboclo dos; LEVY, Debora; MOREIRA, Frederico Rafael; COUTO, Samuel Campanelli Freitas; CULLER, Hebert Fabricio; COSTA, Renata de Oliveira; ROCHA, Vanderson; PEREIRA, JulianaBackgroundSplenic marginal zone lymphoma (SMZL) is a rare lymphoid B-cell malignant neoplasm with primary involvement of the spleen. It is a chronic disease, of indolent behavior and prolonged survival. However, 25% of cases have higher biological aggressiveness, propensity for histological transformation to high grade B-cell non-Hodgkin lymphoma and shortened survival. Recognition of these cases of reserved outcome is important for selecting a risk-adapted therapeutic approach in a resource-poor settings.MethodsWe described clinical and epidemiological characteristics, survival analysis and prognostic factors in a retrospective cohort of 39 SMZL patients, treated in Latin America.ResultsWe observed a predominance of female (71.8%), median age of 63 years and higher incidence of B symptoms (56.4%) and extra-splenic involvement (87.1%) than in European and North-American series. With a median follow-up of 8.7 years (0.6-20.2 years), estimated 5-year overall survival (OS) and progression-free survival (PFS) were 76.9% and 63.7%, respectively. Factors with adverse prognostic impact on OS and PFS were Hb < 100 g/L, platelet count < 100 x 10(9)/L, albumin < 3.5 g/dL, LDH > 480 U/L and high-risk Arcaini and SMZL/WG scores. Despite a relative low number of patients, no superiority was observed among the therapeutic regimens used including rituximab monotherapy, splenectomy and cytotoxic chemotherapy.ConclusionTherefore, in resource-poor settings, where access to immunotherapy is not universal for all SMZL patients, we suggest that first-line should consist on rituximab therapy for elderly patients or with high surgical risk or with at least 1 risk factor identified in our study. Remainders can be safely managed with splenectomy.
- Overexpression of OCT-1 gene is a biomarker of adverse prognosis for diffuse large B-cell lymphoma (DLBCL): data from a retrospective cohort of 77 Brazilian patients(2020) GOUVEIA, Gisele R.; FERREIRA, Suzete C.; SIQUEIRA, Sheila A. C.; LAGE, Luis Alberto de Padua Covas; HALLACK NETO, Abrahao E.; COSTA, Renata de Oliveira; PEREIRA, JulianaBackgroundOCT-1 gene is a member of the POU-homeodomain family of transcriptional regulators of B-lymphocyte differentiation by controlling expression of B-cell specific genes. BCL-2 gene is a potent inhibitor of apoptosis and it is essential during B-cell differentiation into germinal center. These genes may be expressed in diffuse large B-cell lymphoma (DLBCL), but the role of BCL-2 in its prognosis has been contradictory, and OCT-1 has yet to be tested.MethodsIn this study, we aimed to investigate the prognostic impact of OCT-1 and BCL-2 expression in DLBCL treated in the real world with immunochemotherapy in a single center. BCL-2 and OCT-1 genes were available in 78.5% (77/98) DLBCL patients, and the RNA for quantitative real-time PCR was isolated from formalin-fixed paraffin-embedded samples. The values obtained for gene expression were transformed in categorical variable according to their median.ResultsCohort median age was 54.5years (15-84), 49 (50%) were male, 38/77 (49.4%) and 40/77 (51.9%) presented OCT-1 and BCL-2 expression >= median, respectively. The overall response rate (ORR) in all patients was 68.4% (67/98), 65,3% (64/98) of patients acquired complete response, and 3.1% (3/98) partial response, while 6.1% (6/98) were primary refractory. The median follow-up was 3.77years (95% CI: 3.2-4.1), with 5.43 (95% CI: 2.2-NR) of overall survival (OS) and 5.15years (95% CI: 2.9-NA) of progression free survival (PFS). OCT-1 >= median was associated with shorter OS at univariate analysis (p =0.013; [HR] 2.450, 95% CI: 1.21-4.96) and PFS (p =0.019; [HR] 2.270, 95%CI: 1.14-4.51) and BCL-2 gene overexpression presented worse PFS (p =0.043, [HR] 2.008, 95% CI: 1.02-3.95). At multivariate analysis, OCT-1 overexpression was associated with poor PFS (p =0.035, [HR] 2.22, 95% CI: 1.06-4.67).ConclusionIn this study, we showed that overexpression of OCT1 gene was an independent prognostic factor of adverse outcomes in DLBCL.
- Overexpression of the OCT-1 Gene Is a Biomarker Associated with Poor Outcomes in Diffuse Large B-Cell Lymphoma (DLBCL) - Data from a Retrospective Cohort from Latin America: Defining a Very High-Risk Clinical-Molecular Subgroup(2020) LAGE, Luis Alberto de Padua Covas; GOUVEIA, Gisele Rodrigues; FERREIRA, Suzete Cleusa; SIQUEIRA, Sheila Aparecida Coelho de; HALLACK NETO, Abrahao Elias; COSTA, Renata Oliveira; PEREIRA, Juliana
- Cell Cycle Changes, DNA Ploidy, and PTTG1 Gene Expression in HTLV-1 Patients(2020) LEVY, Debora; FERREIRA, Mari Cleia M. R.; REICHERT, Cadiele O.; ALMEIDA, Lis Vilela de; BROCARDO, Graciela; LAGE, Luis Alberto P. C.; CULLER, Hebert F.; NUKUI, Youko; BYDLOWSKI, Sergio P.; PEREIRA, JulianaHuman T-cell lymphotropic virus type-1 (HTLV-1) is a pathogenic retrovirus that is associated with adult T-cell leukemia/lymphoma (ATL). Genetic instability is the hallmark of ATL. Cell cycle progression is needed for virus particle reproduction. HTLV-1 encoded Tax protein ultimately disrupts the mitotic spindle checkpoint, leading to incorrect chromosome segregation, resulting in aneuploidy. Cell cycle abnormalities have been described in T cells transfected with HTLV-1 virusin vitro, but not in HTLV-1 asymptomatic carriers. PTTG1 and HTLV-1 viral protein Tax exhibit a cooperative transforming activity. Overexpressed PTTG1 results in chromosome instability and aneuploidy, which has been suggested as a mechanism underlying PTTG1 transforming activity. Here we aimed to investigate cell cycle, DNA ploidy and PTTG1 mRNA expression in CD4(+)and CD8(+)T cells in healthy subjects (HS), HTLV-1 asymptomatic carriers and ATL patients. We have identified that HTLV-1 asymptomatic carriers have shown DNA aneuploidy and cell cycle arrest at cell cycle phase G(0)/G(1)in CD4(+)T cells. CD8(+)T cells of HTLV-1 asymptomatic carriers also demonstrated DNA aneuploidy but without alteration in cell cycle. In ATL, CD4(+)and CD8(+)T cells present a higher number of cells in cell cycle S-phase and PTTG1 overexpression. These studies provide insight into malignant transformation of HTLV-1 asymptomatic carriers to ATL patients.
- Acquired hemophagocytic lymphohistiocytosis as initial manifestation of multiple myeloma A case report and literature review(2020) MENDES, Fernanda Rodrigues; SOBRAL, Karine Marques; CULLER, Hebert Fabricio; COUTO, Samuel Campanelli Freitas; PEREIRA, Juliana; ROCHA, Vanderson; MARTINEZ, Gracia Aparecida; LAGE, Luis Alberto de Padua CovasIntroduction: Hemophagocytic lymphohistiocytosis (HLH) is a condition characterized by a hyperinflammatory state and persistent macrophage activation, resulting in reactive phagocytosis of the hematopoietic elements. In children, it is usually a hereditary disorder, while in adults it is usually acquired secondary to viral infections, collagenoses, or tumors. Although accounting for 10% of hematologic malignancies, HLH is rarely associated with multiple myeloma (MM) and other plasmacytic dyscrasias. Patient concerns: A 64-year-old Brazilian man seeked medical care with a 3-month history of intermittent fever, weight loss, night sweats, and progressive anemic symptoms. Diagnosis: Total blood count showed severe bicytopenia (normocytic-normochromic anemia and thrombocytopenia), biochemical exams showed elevation of creatinine, as well as monoclonal peak in serum protein electrophoresis, high IgA dosage, and serum immunofixation with IgA kappa paraprotein. Bone marrow biopsy showed 30% of monoclonal and phenotypically anomalous plasmocytes, confirming the diagnosis of MM. Diagnosis of HLH was established by the presence of clinical and laboratory criteria: fever, splenomegaly, cytopenias, hypofibrinogenemia, hyperferritinemia, elevation of triglycerides, and several figures of erythrophagocytosis in bone marrow aspirate. Interventions: The patient experienced pulse therapy with methylprednisolone for hemophagocytic lymphohistiocytosis, followed by initial therapy for multiple myeloma with cyclophosphamide and dexamethasone. Outcomes: Once the diagnosis of MM and secondary hemophagocytic syndrome was established, the patient had a rapid clinical deterioration despite the established therapeutic measures, evolving with cardiovascular failure, acute liver failure, acute disseminated intravascular coagulation, worsening renal dysfunction requiring dialysis support, respiratory dysfunction, and lowering of consciousness, characterizing rapid multiple organ dysfunction, ultimately leading to the death of the patient. Innovation: Here, we aimed to describe the sixth reported case of HLH associated with MM, according to cases cataloged in the PubMed database, and the first case evaluated by 18-fluordeoxyglucose positron emission tomography (18-FDG-PETCT). Conclusion: Our case report seeks to provide support for a better clinical and laboratory characterization of this rare paraneoplastic entity associated with MM, and aims to call the attention of hematologists and intensivists to this condition that falls within the scope of the differential diagnosis of rapid onset multiple organ failure in patients with plasmacytic neoplasms.
- GATA3 Gene - a Potential New Biomarker Associated with Adverse Outcomes in ALK1-Negative Anaplastic Large Cell Lymphoma: Preliminary Results from a Retrospective Cohort of 80 South American Cases of Nodal Peripheral T Lymphoma(2020) LAGE, Luis Alberto de Padua Covas; BRITO, Claudio Vinicius; LEVY, Debora; CULLER, Hebert Fabricio; COUTO, Samuel Campanelli Freitas; ALVES, Lucas B. O.; ZERBINI, Maria C.; ROCHA, Vanderson; PEREIRA, Juliana
- Genetic Subtypes of Systemic Anaplastic Large Cell Lymphoma Show Distinct Differences in PD-L1 Expression and Regulatory and Cytotoxic T Cells in the Tumor Microenvironment(2020) FERREIRA, Cristiane R.; MANOHAR, Vidhya; ZHAO, Shuchun; BANGS, Charles D.; CHERRY, Athena; AZEVEDO, Raymundo Soares; LAGE, Luis A. P. C.; PEREIRA, Juliana; ZERBINI, Maria C. N.; GRATZINGER, Dita; NATKUNAM, YasodhaAnaplastic large cell lymphomas (ALCL) encompass several subgroups that differ in their clinical presentation, genetic features, and prognosis. We characterized the genetic subgroups of 74 patients with ALCL and correlated programmed death ligand 1 (PD-L1) protein expression and compared the densities and ratios of FOXP3+ T regulatory cells and CD8+ tumor-infiltrating lymphocytes (TILs) in tumor cells and the immune microenvironment. The subgroups included anaplastic lymphoma kinase (ALK)-positive (ALK+) ALCL and ALK-negative (ALK-) ALCL and DUSP22-rearranged and nonrearranged ALK- ALCL. None of our cases represented the TP63-rearrangement ALK- ALCL subgroup. Our results showed that ALK+ ALCL had a higher expression of PD-L1 in the tumor cells, in contrast to ALK- ALCL, which expressed high PD-L1 in tumor-associated macrophages (TAMs). DUSP22-rearranged ALK- ALCL lacked PD-L1 expression in the tumor cells and instead expressed PD-L1 only in TAMs. There was a significant positive correlation of PD-L1 expression between tumor and TAMs in ALK+ ALCL with a negative correlation in ALK- ALCL. Systemic ALCL subgroups had similar densities of CD8+ tumor-infiltrating lymphocytes and FOXP3 T regulatory cells, but differences were observed in the ratio of CD8/FOXP3. Our results suggest that alterations in tumor microenvironment and immune responses exist among systemic ALCL subgroups and these features may account for different clinical behavior and prognosis.